The invention relates generally to systems and methods for measuring low volume flows of liquid and relates more particularly to non-invasively measuring flow rates within liquid analysis systems and drug delivery systems that require a high degree of flow measurement accuracy in extremely low volume applications.
Accurate measurements of low volumetric liquid flow rates are important in many analytical applications, such as flow injection analysis, micro-bore liquid chromatography, capillary chromatography, capillary electrophoresis, and bioassay applications. Precise measurements are also important in drug delivery applications. The flow rate in analytical systems may be in the range of 0.0001 milliliter/minute (ml/min) to 1 ml/min. In medical applications, the flow rate may be as low as 0.008 ml/min for ambulatory infusion. In addition to accuracy, other concerns in selecting an approach for measuring flow rate include providing a fast dynamic response and minimizing the risk of introducing contamination into the flow of liquid.
The most common approaches to measuring flow rate incorporate a heater and at least one temperature-sensitive resistor within the flow channel. In a thermal transit-time approach, the heater is supplied with a signal, such as a square-wave voltage at a selected frequency, to inject heat pulses as tracers into the fluid of interest. The periodic heat tracers travel along the flow channel, causing periodic temperature fluctuations downstream. The heat tracers are detected by a thermistor or other temperature sensing device that is located within the flow. In steady state, the phase shift of the downstream thermal fluctuations relative to the upstream thermal fluctuations are related to the mean velocity of the fluid. This approach has little dependency on the ambient temperature and on the properties of the liquid, so that the transit time can be determined accurately.
In a thermal dilution flow approach, three resistors may be located along a flow channel, with the center resistor being used as the heater and the end resistors being used as temperature-sensitive members. Current is passed through the heater to trigger a change in temperature within the liquid flow. The two temperature-sensitive resistors are located equidistantly from the heater resistor and are used to sense the heat distribution from the center. Flow rate is determined as a function of the temperature difference between the upstream and downstream temperature-sensitive resistors.
One approach that does not utilize temperature-sensitive members is the differential pressure flow approach. In laminar flow conditions with low Reynolds numbers, the pressure difference across an orifice is proportional to the flow rate.
There are a number of concerns with these conventional approaches to determining flow rate. A first concern is that contact with the flowing liquid will introduce contamination into the stream. A contamination-free approach to determining flow rate is important in chemical analysis applications and drug delivery applications. Another concern is that the approaches may not be sufficiently sensitive at extremely low flow rates.
Systems for measuring liquid flow rates without contacting the liquid are described in U.S. Pat. No. 5,764,539 to Rani and U.S. Pat. No. 4,938,079 to Goldberg. In Rani, a pump is operated to deliver a fluid in pulses. The fluid flows through a fluid delivery tube. A sensor is in contact with the outer surface of the fluid delivery tube in order to detect the temperature of the outer surface. The sensor is calibrated at an initial temperature and is responsive to the flow of fluid through the tube. Since fluid flow will increase the temperature at the outer surface of the tube, the output of the temperature-sensitive sensor is indicative of the flow rate through the tube. While the Rani system may operate as designed, the sensitivity of the measurements may not be sufficient at the flow rates associated with many analytical systems and medical applications. Moreover, the pulsed deliveries may not be desirable in many applications.
The Goldberg system utilizes microwave energy to determine flow rates. A thermal marker is introduced into the flow of liquid to be measured. For example, a heat pulse may be generated by radiating energy into the stream using a microwave heating device. An alternative means of introducing the thermal marker is through the use of focused infrared energy produced by a laser or other source. The flow rate may be measured by determining the transit time of the thermal marker from the heater to a sensor. In the preferred embodiment, the liquid conduit is passed through a resonant microwave cavity such that the resonant characteristics of the cavity are affected by the passage of the thermal marker. For example, the dielectric constant of the liquid will change with temperature, so that the resonant frequency of the microwave cavity will vary with passage of the thermal marker through the cavity. The Goldberg system is designed to provide accuracy at flow rates below 100 cc/hour. However, the use of microwave signals limits the sensitivity of the system. As a consequence, the Goldberg system is not easily adapted to use in micro fabricated devices and micro analysis systems.
U.S. Pat. No. 5,726,357 to Manaka and U.S. Pat. No. 5,623,097 to Horiguchi et al. describe micro fabricated devices which employ the thermal approaches described above. Thus, the flow sensors are highly sensitive, but directly contact the flowing fluid. In Manaka, a substrate is patterned to include a heating portion and a sensing portion. The transit time for heat transfer from the heating portion to the sensing portion is used to calculate flow rate. Similarly, the Horiguchi et al. sensor includes a substrate through which a fluid path is formed. A bridge is suspended over the fluid path. A heating resistor and a temperature sensor are formed on the bridge through an interlayer isolating film that is designed to eliminate the difference between the temperature of the heater and the heat sensor. A temperature compensating circuit may be used to offset any remaining effects of thermal communication between the heater and the temperature sensor.
While known approaches operate as designed, what is needed is a system and a method for monitoring fluid flow in a manner that does not introduced contamination into the flow and that is easily adapted to applications having a small cell volume.
A system for measuring flow rate within a fluid-bearing passageway includes introducing a heat tracer into the flow and includes non-invasively and indirectly monitoring the effects of the heat tracer as it propagates to one or more interrogation regions. Typically, the heat tracer is one thermal fluctuation introduced by a modulating heat generator. In one embodiment, the non-invasive monitoring occurs optically. In another embodiment, the electrical conductivity of the fluid is monitored. Based upon the detection of changes in the physical properties of the fluid that propagates through interrogation regions, the rate of flow of the fluid is identified. For example, the phase shift between the modulations of the heat generator and the modulations of temperature-dependent physical properties (optical or electrical) may be used to determine flow rate.
In any of the embodiments, the heat tracer may be introduced using an optical heat generator. For example, the heat generator may include an infrared laser, infrared lamp or a light emitting diode (LED) that generates a beam that is incident to the flow of fluid through a capillary or a micro channel of a micro analytical device. In an alternative embodiment, the heat generator is a coil that is in thermal communication with the passageway, but is removed from direct contact with the fluid.
At least one temperature-dependent property of the fluid is measured upstream of the heat generator, downstream of the heat generator, or both. Thus, the temperature of the fluid is not detected directly. For the optical sensing embodiment, the effects of fluctuations in the refractive index of the fluid sensed. For example, the system can monitor changes in a back-scattered or forward-scattered interference pattern generated as a result of light interacting with the fluid and the structure of the passageway. On the other hand, the electrical sensing embodiment forms a capacitive cell for monitoring resistivity.
In the optical sensing embodiment, the detector includes an optical arrangement having a light source which is spatially removed from the fluid-bearing passageway, while being optically coupled to the passageway at the interrogation region. Typically, the interrogation region is downstream of the heat generator, but the interrogation region may be coincident with the heating region, so that heat tracers are monitored as temperature fluctuations within the interrogation region in which they are introduced. As another alternative, a second interrogation region may be included upstream of the heat generator, particularly if a thermal dilution flow approach is utilized. Regardless of the position of an interrogation region, if the heat tracers are introduced in a repeating pattern (e.g., sine wave pattern), the modulations of the temperature-dependent physical properties of the fluid are used to determine flow rate.
At each interrogation region, a detector is positioned to receive light energy originating from the associated light source and redirected at the interrogation region as a result of interaction with the passageway and with the fluid in the passageway. The detector has an output that is responsive to the reception of light energy. In one application, the detector is positioned to detect an interference pattern generated by light interacting with the fluid and light interacting with the passageway. As is well known in the art, the back-scattered interference pattern may be formed as a consequence of constructive and destructive interference when light is reflected at both the xe2x80x9cforwardxe2x80x9d fluid-to-passageway interface and the xe2x80x9crearwardxe2x80x9d fluid-to-passageway interface. The phase difference between the two reflections determines the characteristics of the interference pattern. Since the phase shift will vary with changes in the refractive index of the fluid and since the refractive index will vary with changes in temperature of the fluid, the interference pattern is responsive to the temperature of the fluid. A similar interference pattern is generated by the forward-scattered light and may alternatively be used.
The detector may have a field of view that is sufficiently large to detect a number of minima and maxima of the interference pattern. Alternatively, the detector may be an optical fiber or other single element sensing arrangement having an aperture with a size that is insufficient to detect adjacent minima or adjacent maxima in the intensity modulated profile of the interference pattern. The single-element sensing arrangement provides a less expensive and less complex detector than would be necessary if multiple minima and maxima were imaged.
As an alternative to detecting the interference pattern, the optical embodiment may be implemented by placing the detector to sense light energy that propagates through the fluid. The angle of the axis of the exiting beam is dependent upon the refractive index of the fluid. Consequently, the position of the exit beam can be used to determine when a heat tracer passes the interrogation region.
In the optical embodiments, the interrogating light source that is directed into the fluid is preferably a xe2x80x9cnon-thermal beam.xe2x80x9d A non-thermal beam will be defined herein as one that experiences a low absorbency during propagation through the fluid. A beam having a center frequency below 1100 nm (i.e., at or below the near infrared) is typically non-thermal.
In the second embodiment of the invention, the resistivity of the fluid within the passageway is monitored to detect when a heat tracer propagates through an interrogation region. In the same manner as the optical embodiments, the time required for passage of a heat tracer from the heat generator to the interrogation region is used to calculate flow rate. For a repeating pattern of heat tracers, the phase difference between the introduction of the heat tracers (i.e., thermal fluctuations) and resistivity fluctuations may be utilized. Resistivity (and therefore conductivity) of the fluid may be monitored by placing electrodes adjacent to the outside wall of the passageway and supplying a high frequency signal to the electrodes, thereby forming a capacitive cell. For almost all liquids having a non-zero level of conductivity at a particular temperature, the resistivity will decrease with increases in temperature. As a result, monitoring the resistivity provides a reliable means for detecting the time at which a heat tracer reaches the interrogation region of the passageway.
While not critical, the system and method are easily adapted to use with micro fabricated devices. The heaters and optical components may be coupled to the same substrate as micro machined valving components. Consequently, the system may be integrated into a micro analysis system or a micro-drug delivery and dosing system. The fluid-bearing passageway may be a capillary used in capillary chromatography or capillary electrophoresis. Flow rates as low as 0.0001 ml/min may be accurately measured.
One advantage of the invention is that the system and method may be used in applications having extremely small cell volumes, such as those used in micro analytical devices, since there is no need for making contact between a probe and the liquid of interest. Another advantage is that the system does not introduce contamination into the fluid, since direct contact is avoided. Yet another advantage is that substrate temperature does not need to be measured, because the substrate temperature does not contribute to the measurement of flow rate. In many known uses of thermal sensors to monitor temperature directly, the substrate temperature is a factor and temperature compensation is used to offset the effects of thermal radiation from the heater to the sensor. By utilizing a method that does not directly measure temperature, any direct radiation from the heater to the sensor of the present invention does not affect the calculation of flow rate. Furthermore, there is no heat loss from the fluid to the detector, as there would be if the system required the detector to be thermo-coupled to the fluid. Additionally, the method is more readily adaptable for use in micro flow applications, as compared to methods that utilize temperature sensors to detect heat tracers. There are difficulties associated with fabricating and coupling heat sensors that are sufficiently small and sufficiently sensitive for micro flow applications.
Optionally, the system may be used to control the liquid temperature within the fluid-bearing passageway. The measurement of temperature-dependent physical properties of the liquid flow may be used to monitor liquid temperature and to provide a feedback control of the heater.
As other options, the interrogation region may be coincident with the region in which the heat tracers are introduced (as noted above) or a non-thermal tracer can be substituted for the heat tracer. For example, the composition of the fluid, which also affects the refractive index, may be intentionally fluctuated to provide a non-thermal means for determining flow rate.